US10913757B2 - Hydroxycinnamic derivatives, methods and uses thereof - Google Patents

Hydroxycinnamic derivatives, methods and uses thereof Download PDF

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US10913757B2
US10913757B2 US16/342,083 US201716342083A US10913757B2 US 10913757 B2 US10913757 B2 US 10913757B2 US 201716342083 A US201716342083 A US 201716342083A US 10913757 B2 US10913757 B2 US 10913757B2
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antioxcin
compound
chain
mitochondrial
aryl
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Maria Fernanda MARTINS BORGES
Paulo Jorge GOUVEIA SIMÕES DA SILVA OLIVEIRA
JoséCarlos Santos Teixeira
Fernando Cagide Fagin
Ester Sofia TEIXEIRA BENFEITO
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Universidade do Porto
Centro de Neurociencias e Biologia Celular
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    • A—HUMAN NECESSITIES
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Definitions

  • the present disclosure relates to the design and development of new hydroxycinnamic derivatives that operate as mitochondriotropic antioxidants. Furthermore, this disclosure is also related to the methods and uses of the hydroxycinnamic derivatives, for example, in the field of human and animal diseases, for instance to treat mitochondrial dysfunction or mitochondrial deficiencies, and cosmetics, for instance to prevent or delay skin aging.
  • Oxidative stress is a very complex process, which impacts biological systems in different aspects. Its impact on biological systems depends on the type of oxidant agent involved, on the site and intensity of its production, on the composition and activities of endogenous antioxidants, and on the activity of repair systems Oxidative stress can alter redox signalling in cells disrupting the normal homeostasis, which in some cases can lead to major cellular damage, thus being connected with a number of diseases, namely those associated with aging. 1,2
  • exogenous antioxidants may in theory block the complex networks of oxidative damage pathways at different levels, yielding an therapeutic effect. Consequently, antioxidants that are exogenously acquired from diet may have important functions in redox cell homeostasis and can be important for cellular function and disease prevention.
  • Antioxidants have been defined as any substance that when present at low concentrations, compared to those of an oxidizable substrate, significantly delays or prevents the oxidation of biomolecules. Antioxidants may exert their effects by different mechanisms, such neutralizing circulating reactive species (scavenging activity), sequestering transition metal ions (chelation activity) and inhibiting enzymes involved in the production of reactive species. 1,2 Moreover antioxidants may also increase the expression or activity of endogenous antioxidant systems.
  • antioxidants per se or in combination with other drugs, is considered to be beneficial for the prevention/minimization of deleterious events related with oxidative-stress, namely in associated diseases or processes 1 .
  • Phenolic compounds are one of the most important classes of natural antioxidants present in the human diet. Epidemiological studies and associated meta-analyses suggested that the long-term consumption of diets rich in phenolic rich foods or beverages has a positive outcome in the incidence of oxidative-stress-related diseases 2 .
  • HCAs Hydroxycinnamic acids
  • caffeic and coumaric acid are the most abundant in fruits accounting for between 75 and 100% of the total HCAs content.
  • the dietary intake of HCAs has been estimated to be a total of 211 mg/day.
  • the intake of caffeic acid alone was reported to be 206 mg/day, being coffee, fruits and their juices the main dietary sources 2 .
  • Hydroxycinnamic acids exhibit a wide range of biological activities. They are well-known by their antioxidant properties that are related with diverse action mechanisms, namely direct free radical scavenging activity and/or other indirect actions, including the chelation of pro-oxidant transition metals (namely copper and iron), modulation of gene expression (e.g. ARE/Nrf2 pathway) and inhibition of radical generating enzymatic systems 2 .
  • Phenolic natural antioxidants like hydroxycinnamic acids, have enjoyed general success in preclinical studies but still have little benefit in human intervention studies or clinical trials. In clinical trials over the past years no positive/relevant results were obtained so far. Most studies showed that some of them lacked any therapeutic advantage. In fact, a significant mismatch between the results obtained in pre-clinical studies and the outcome of clinical trials exists. This gap may be related not only with the protocol used in clinical trials but also by pharmacokinetics restrains of the antioxidants under evaluation assessment. Similarly to other natural or dietary antioxidants they have bioavailability drawbacks being unable to cross biological barriers and reach intracellular target sites 2 .
  • antioxidants may alter the normal redox balance in particular cell compartments, which will make more harm than good.
  • Another possibility is that some of the antioxidants do not reach the relevant places of free radical generation, namely mitochondria that are actually the primary source of reactive oxygen species (ROS) and oxidative damage 1,2 .
  • ROS reactive oxygen species
  • Mitochondrial function and specifically its impact in cellular redox/oxidative balance, is fundamental for controlling cellular life and death. Besides being the major source of chemical energy to the cell, mitochondria are involved in the production and detoxification of ROS, in the regulation of multiple signalling pathways related with cellular homeostasis, including cell survival, redox balance and cell death 3,4 . Although ROS production is tightly regulated by an endogenous antioxidant network, its disruption can lead to mitochondrial oxidative damage and dysfunction. Mitochondrial oxidative dysfunction impairs multiple metabolic and signalling pathways and can trigger cell death via apoptosis or necrosis.
  • TPP triphenylphosphonium
  • Mitoquinone (MitoQ, MitoQ 10 , [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methanesulfonate).
  • MitoQ is constituted by an endogenous antioxidant moiety (coenzyme Q) covalently linked to a 10-carbon alkyl chain (dTPP) spacer and to a triphenylphosphonium (TPP) cation.
  • MitoQ is under clinical trials for different pathologies, namely for hepatitis C. Yet, clinical trials using MitoQ as a therapeutic solution for neurodegenerative diseases have produced disappointing results.
  • SKQ1 10-(4,5-dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl)triphenylphosphonium bromide
  • SkQ1 was shown to decrease oxidative stress inside mitochondria and significant protecting benefits for dry eye condition.
  • TPP mitochondrial-directed antioxidant based on caffeic acid
  • the compound here named as AntiOxCIN 1 preserved the parent compound antioxidant activity while being more lipophilic.
  • AntiOxCIN1 accumulated in mitochondria and protected mouse myoblast C2C12 cells against different oxidative stress stressors, namely H 2 O 2 and linoleic acid-hydroperoxides
  • AntiOxCIN1 efficacy as mitochondriotropic antioxidant was far from desired.
  • Mitochondria and the control of the cellular reactive oxygen species (ROS) and redox balance, are an attractive target for drug discovery and development. Targeting mitochondria with modulator agents has proven to be an effective strategy.
  • ROS reactive oxygen species
  • Targeting mitochondria with modulator agents has proven to be an effective strategy.
  • the rational design of potent and effective mitochondriotropic antioxidants (AntiOxCINs) based on hydroxycinnamic acids was performed.
  • the present disclosure in a first aspect, is related to the development of new hydroxycinnamic derivatives that may be identified by the general formula
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from each other;
  • R 1 , R 2 , R 3 , R 4 and R 5 are selected from H, halogen, hydroxyl, methyl, methoxyl, amino, carboxylic acid, or nitro group;
  • R 6 , R 7 , R 8 are an alkyl chain, an alkenyl chain, an alkynyl chain, a substituted aryl or a cyclic ring;
  • a bond between R 6 and R 7 is a single bond, a double bond or a triple bond and with the proviso that wherein the bond between R 6 and R 7 is a double bond, R 3 ⁇ R 2 are different from OH, and R 1 ⁇ R 4 are different from H, and R 6 ⁇ R 7 are different from methyl, and Z ⁇ is an anion.
  • an alkyl group is defined as a univalent group derived from alkanes by removal of a hydrogen atom from any carbon atom —C n H 2n+1 .
  • the groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups H (CH 2 ) n .
  • the groups RCH 2 , R 2 CH (R ⁇ H), and R 3 C (R ⁇ H) are primary, secondary and tertiary alkyl groups, respectively.
  • An aryl group is derived from arenes (monocyclic and polycyclic aromatic hydrocarbons) by removal of a hydrogen atom from a ring carbon atom.
  • Alkyl includes “lower alkyl” and extends to cover carbon fragments having up to 30 carbon atoms.
  • alkyl groups include octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, 2-(cyclododecyl)ethyl, adamantyl, and the like.
  • Lower alkyl means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, cyclopropylmethyl, and the like.
  • Halogen is an element selected from the list consisting of: F, Cl, Br, I, At.
  • the bond between R 6 and re may be a single bond or a double bond, with the proviso that wherein the bond between R 6 and R 7 is a double bond, R 3 ⁇ R 2 are different from OH, and R 1 ⁇ R 4 are different from H, and R 6 ⁇ R 7 are different from methyl.
  • the alkyl chain, the alkenyl chain or the alkynyl chain may be a C 1 -C 30 chain, preferably a C 1 -C 18 chain, more preferably a C 2 -C 14 chain, even more preferably a C 3 -C 12 chain or a C 6 -C 10 chain.
  • the alkyl chain may be a C 6 alkyl chain, a C 7 alkyl chain, a C 8 alkyl chain, a C 9 alkyl chain, or a C 10 alkyl chain.
  • the substituted aryl may be an alkane-aryl substituted, alkene-aryl substituted, or alkyne-aryl substituted preferably C 6 -C 10 -aryl, preferably phenyl; benzyl, phenethyl, phenpropyl, phenbutyl or phenhexyl, which is optionally substituted once or several times by:
  • the cyclic ring may be a cyclopropane, cyclobutane, cyclopentane, or cyclohexane.
  • the Z ⁇ anion is selected from the following list: alkyl sulfonate, aryl sulfonate, nitrate or a halogen, wherein said halogen may be F, Cl or Br; the alkyl sulfonate or aryl sulfonate may be selected from the following list: methanesulfonate, p-toluenesulfonate, ethanesulfonate, benzenesulfonate and 2-naphthalenesulfonate.
  • R 1 , R 2 , R 3 , R 4 and R 5 may comprise an halogen, wherein said halogen is F, Cl or Br.
  • R 1 and R 5 may be H.
  • R 2 and R 3 may be OH.
  • R 4 may be H or OH.
  • R 6 and R 7 may be a C 1 alkyl chain.
  • R 8 may be a C 2 alkyl chain.
  • the compound may be (E)-(6-(3-(3,4-dihydroxyphenyl)prop-2-enamido)hexyl)triphenylphosphonium methanesulfonate.
  • the compound may be (E)-(8-(3-(3,4-dihydroxyphenyl)acrylamido)octyl)triphenylphosphoniummethanesulfonate.
  • the compound may be (E)-(6-(3-(3,4,5-trihydroxyphenyl)prop-2-enamido)hexyl)triphenylphosphonium methanesulfonate.
  • the compound may be (E)-(8-(3-(3,4,5-trihydroxyphenyl)acrylamido)octyl)triphenylphosphonium methanesulfonate.
  • the compound may be (E)-(10-(3-(3,4-dihydroxyphenyl)acrylamido)decyl)triphenylphosphonium methanesulfonate.
  • the present disclosure also relates to any compound, or related ones, now disclosed for use in medicine or veterinary.
  • the disclosed compounds, or related ones may be used for modulating at least one aspect of mitochondrial morphology and/or expression of OXPHOS enzymes.
  • the disclosed compounds, or related ones may be used for the treatment or prevention or suppression of symptoms associated with a mitochondrial disorder or with a condition associated with mitochondrial dysfunction in general, including diseases originated from mitochondrial respiratory chain defects.
  • the mitochondrial disorder is a disorder selected from the group consisting of: Myoclonic epilepsy; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Leber's Hereditary Optic Neuropathy (LHON); neuropathy ataxia and retinitis pigmentosa (NARP); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Leigh syndrome; Leigh-like syndrome; Dominant Optic atrophy (DOA); Kearns-Sayre Syndrome (KSS); Maternally Inherited Diabetes and Deafness (MIDD); Alpers-Huttenlocher syndrome; Ataxia Neuropathy spectrum; Chronic Progressive External Ophthalmoplegia (CPEO); Pearson syndrome; Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE); Sengers syndrome; 3-methylglutaconic aciduria, sensorineural deafness, encephalopathy and neuro-radiological findings of Leigh-like syndrome
  • the condition associated with mitochondrial dysfunction may be a disorder selected from the group consisting of: Friedreich's Ataxia (FRDA); renal tubular acidosis; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); Huntington's disease; developmental pervasive disorders; hearing loss; deafness; diabetes; ageing; and adverse drug effects hampering mitochondrial function.
  • FRDA Friedreich's Ataxia
  • ALS amyotrophic lateral sclerosis
  • Huntington's disease developmental pervasive disorders
  • hearing loss deafness
  • diabetes ageing
  • adverse drug effects hampering mitochondrial function may be a disorder selected from the group consisting of: Friedreich's Ataxia (FRDA); renal tubular acidosis; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); Huntington's disease; developmental pervasive disorders; hearing loss; deafness; diabetes; ageing; and adverse drug effects hampering mitochondrial function.
  • FRDA Fried
  • the compounds now disclosed, or related ones may be for use in the treatment or prevention of a neurodegenerative disease, neoplasia, kidney disease, scleroderma, hepatic iron overload disease, hepatic copper overload disease, alopecia, human infertility, acute pancreatitis, fibromyalgia, or other disease related with the involvement of mitochondrial oxidative disease.
  • the compounds now disclosed, or related ones may be for use in the treatment of non-alcoholic fatty liver diseases, namely non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or hepatic cirrhosis, among others.
  • non-alcoholic fatty liver diseases namely non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or hepatic cirrhosis, among others.
  • the compounds now disclosed, or related ones may be for use in neoplasias, namely wherein the neoplasia disease is a cancer, in particular basal cell carcinoma, bone cancer, bowel cancer, brain cancer, breast cancer, cervical cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer or biliary cancer, among others.
  • a cancer in particular basal cell carcinoma, bone cancer, bowel cancer, brain cancer, breast cancer, cervical cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer or biliary cancer, among others.
  • the compounds now disclosed, or related ones may be for use in kidney related diseases namely, kidney failure, among others.
  • the compounds now disclosed, or related ones may be for use in amyotrophic lateral sclerosis.
  • the compounds now disclosed, or related ones may be for use as antimicrobial agent, in particular as a disinfectant.
  • the compounds now disclosed, or related ones may be for use in the maintenance of a pluripotent cell culture, as a supplement for cell culture in particular as growth medium component.
  • the compounds now disclosed, or related ones may be for use for accelerating muscle recovery after physical exercise.
  • the compounds now disclosed, or related ones may be used as active ingredients on cosmetic, supplement or nutraceutical products, namely as an anti-aging or anti-wrinkle skin care ingredient or product.
  • This disclosure also relates to a cell culture medium for maintaining pluripotent stem cells in an undifferentiated state comprising any of the compounds, or related ones, now disclosed.
  • This disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds, or related ones, now disclosed and one or more pharmaceutically acceptable carrier, adjuvant, excipient, diluent or mixtures thereof, among others.
  • the adjuvant may be selected from the following list: oil-in-water emulsion adjuvant, aluminium adjuvant, a TLR-4 ligand, a saponin, and mixtures thereof, among others.
  • the pharmaceutical composition may be topically, orally, parenterally or injectable administrated.
  • the pharmaceutical composition may be for use, for example, in a method for the treatment or prevention of a neurodegenerative disease, non-alcoholic fatty liver disease, neoplasia, kidney disease, scleroderma, hepatic iron overload disease, hepatic copper overload disease, alopecia, human infertility, acute pancreatitis or fibromyalgia, wherein the pharmaceutical composition is administered in a daily dose.
  • This disclosure also provides a nanocarrier, for instance a liposome, wherein said nanocarrier or said a liposome comprise the compounds, or related ones, or the pharmaceutical composition, now disclosed.
  • the composition may comprise the compounds disclosed, or related ones, in the present subject-matter, in an amount effective to improve the efficacy of other therapies, including immunotherapy or any pharmacological approach, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 95.7%, at least 98%, or at least 99% in the subject.
  • the composition comprises a dose of 0.1-1000 mg.
  • the preparation comprises a dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg,
  • the composition comprises a dose of 0.1-10 mg/kg, 0.1-100 mg/kg, 1-10 mg/kg, 1-100 mg/kg, 1-1000 mg/kg, 10-100 mg/kg, 10-1000 mg/kg, 100-1000 mg/kg, 10-50 mg/kg, 10-25 mg/kg, 10-20 mg/kg, 50-100 mg/kg, or 100-250 mg/kg.
  • Preferred routes of administration include but are not limited to oral, parenteral, intramuscular, intravenous, in situ injection, intranasal, sublingual, intratracheal, inhalation or topical.
  • FIG. 1 Synthetic strategy pursued to obtain a number of AntiOxCINs.
  • Reagents and conditions i) Ethyl chloroformate, aminoalcohol, r.t.; ii) Methanesulfonyl chloride, r.t.; iii) Triphenylphosphine, 150° C. (microwave, 1 h 30 min) or 130° C. (18 h); or iv) BBr3, from ⁇ 70° C. (10 min) to r.t. (12 h).
  • FIG. 2 Evaluation of iron chelating properties of caffeic acid, AntiOxCINs and MitoQ.
  • EDTA chelating agent
  • FIG. 3 (A) AntiOxCINs uptake by energised rat liver mitochondria measured using a TPP-selective electrode. (B) AntiOxCINs aromatic ring pattern substitution and alkyl carbon side chain effects on lipophilicity (---) and mitochondrial accumulation ratio (—). (C) AntiOxCINs accumulation ratio by rat liver mitochondria. MIT, mitochondria; SUC, succinate; VAL, valinomicin.
  • FIG. 4 Effect of caffeic acid, AntiOxCINs and MitoQ on mitochondrial lipid peroxidation under different oxidative conditions: (A) TBARS levels and (B) changes on oxygen consumption. The comparisons between control vs. AntiOxCINs (5 ⁇ M) pre-incubations were performed by using one-way ANOVA.
  • FIG. 5 Effect of (A) caffeic acid, (B) dTPP and MitoQ, and AntiOxCINs containing a (C) catechol or (D) pyrogallol core on lipid peroxidation of RLM membranes induced by ADP and Fe 2+ followed by oxygen consumption.
  • FIG. 7 Effect of AntiOxCINs and MitoQ on mitochondrial swelling upon induction of the mitochondrial permeability transition pore (mPTP).
  • AntiOxCINs and MitoQ at (A) 2.5 ⁇ M, (B) 5 ⁇ M and (C) 10 ⁇ M were pre-incubated with RLM for 5 min before calcium addition. The comparisons were performed using one-way ANOVA between control (Ca 2+ only) vs. assays where AntiOxCIN derivatives were pre-incubated before Ca 2+ .
  • FIG. 8 (A) Cytotoxicity profile of AntiOxCIN 4 ( ⁇ ) and AntiOxCIN 6 (•) on hepatocellular carcinoma cells (HepG2). Statistically significant compared with control group using one-way ANOVA (B) Effect of AntiOxCIN 4 and AntiOxCIN 6 on iron- and hydrogen peroxide-induced damage of HepG2 cells. The comparisons were performed by using one-way ANOVA between the control (FeSO 4 or H 2 O 2 ) vs. preparation where AntiOxCINs were pre-incubated (C) AntiOxCIN 4 and AntiOxCIN 6 (100 ⁇ M and 2.5 ⁇ M, respectively) did not disturb the normal nuclear morphology and mitochondrial polarization.
  • FIG. 1 the synthetic strategy pursued for the development of a number of cinnamic lipophilic cationic antioxidants (AntiOxCINs) is depicted in FIG. 1 .
  • the di (1) or trimethoxycinnamic (2) acids used as starting materials were linked by an amidation reaction to suitable bifunctionalized alkyl spacers with a variable length (cinnamic derivatives 3-8). Then, the alcohol functions of the derivatives were activated with a leaving group (—OSO 2 CH 3 ) to obtain the cinnamic derivatives 9-14.
  • the AntiOxCINs antioxidant, redox and lipophilic properties were reported.
  • Caffeic acid and AntiOxCIN 1 were also included in the study. The results were depicted in Table 1.
  • the AntiOxCINs antioxidant ranking activity hierarchy was established by in vitro non-cell methods.
  • the selected total antioxidant capacity (TAC) assays (DPPH, ABTS and GO) involved the spectrophotometric measurement of the radical absorbance decrease as a result of an in situ radical deactivation by an antioxidant. Compounds with higher antioxidant activity display lower IC 50 values.
  • the antioxidant data (Table 1) allow concluding that AntiOxCINs are effective antioxidants, when compared with caffeic acid and AntiOxCIN 1 , and that the attained IC 50 values followed the same trend in the three different assays.
  • AntiOxCIN 4 , AntiOxCIN 5 and AntiOxCIN 7 have a similar, or superior, antioxidant activity than caffeic acid and AntiOxCIN 1 .
  • the chemical changes performed in the spacer length do not have a negative influence in the radical-scavenging ability. On contrary a higher antioxidant capacity was observed for compounds that have a lengthy alkyl spacer.
  • AntiOxCINs redox properties were evaluated (Table 1). Redox potentials are correlated with the ability of an antioxidant to donate a hydrogen atom and/or an electron to a free radical. Generally, low oxidation potentials (Ep) are associated with a superior antioxidant performance.
  • E p pyrogallol derivatives
  • cyclic voltammetry data allowed concluding that caffeic acid and its catechol analogues (AntiOxCIN 1 , AntiOxCIN 2 , AntiOxCIN 3 and AntiOxCIN 6 ) suffer a reversible reaction, as a single anodic peak and one cathodic peak in the reverse scan was observed.
  • the oxidation mechanism was comparable to that proposed for caffeic acid as it involved two electrons per molecule, which likely corresponded to the formation of a semiquinone radical and its subsequent oxidation to ortho-quinone.
  • pyrogallol systems appear to suffer an irreversible oxidation reaction as any reduction wave was seen on the cathodic sweep.
  • AntiOxCIN 4 AntiOxCIN 5 and AntiOxCIN 7
  • the voltammograms presented a diffusion peak and an adsorption post-peak at a more anodic potential correspondent to the oxidation of dissolved and adsorbed forms of the compounds, respectively.
  • the oxidation waves can be related to the oxidation process of the pyrogallol moiety.
  • the cyclic voltammograms also show the presence of two overlapped anodic peaks.
  • the data attained with TAC assays is consistent with AntiOxCINs redox outline. Overall the results reinforce the assumption that the number of hydroxyl substituents present on the cinnamic aromatic ring is directly related with the antioxidant and electrochemical properties.
  • AntiOxCINs lipophilic properties were evaluated at physiological pH by electrochemistry.
  • the used technique is often used to mimic the transfer of ionic drugs through biological membranes as the process occurs at the interface between two immiscible electrolyte solutions (ITIES).
  • DPV differential pulse voltammetry
  • the transfer potential (E tr ) becomes less positive with the increasing of the drug lipophilic character.
  • the AntiOxCINs transfer potentials (E tr ) obtained are shown in Table 1.
  • an increment of AntiOxCINs lipophilicity was observed as function of the length of the alkyl spacer. This behaviour was observed in both AntiOxCINs series, being AntiOxCIN 1 the less lipophilic compound. As expected, caffeic acid does not permeate.
  • the relative lipophilicity increased in the following order: AntiOxCIN 1 ⁇ AntiOxCIN 2 ⁇ AntiOxCIN 3 ⁇ AntiOxCIN 6 and for pyrogallol based series: AntiOxCIN 4 ⁇ AntiOxCIN 5 ⁇ AntiOxCIN 7 .
  • the introduction of an additional OH function increased AntiOxCINs hydrophilicity.
  • AntiOxCINs chelating properties namely their ability to chelate iron, were determined.
  • Iron is a redox active metal that can catalyse Fenton and Haber-Weiss reactions generating hydroxyl radicals (*OH), which is a strong oxidant species that is linked with oxidative damage events with severe implications for human health and disease.
  • *OH hydroxyl radicals
  • loss of mitochondrial iron homeostasis and consequent iron overload can contribute to mitochondrial dysfunction and in turn to different pathologies. So, the use of metal chelating agents, or antioxidants that operate by this or more than one mechanism can function as a therapeutic approach to prevent metal-induced toxicity.
  • AntiOxCINs iron (II) chelating properties were evaluated by the ferrozine assay using ethylenediaminetetracetic acid (EDTA) as reference.
  • EDTA ethylenediaminetetracetic acid
  • the iron chelating properties of caffeic acid and MitoQ were also evaluated.
  • EDTA was found to be able to chelate all the iron in solution as it can inhibit completely the formation of the colored ferrozine-fe(II) complex.
  • AntiOxCINs catechol or pyrogallol series
  • caffeic acid in opposition to MitoQ, were able to chelate ferrous iron alike EDTA ( FIG. 2 ).
  • the new derivatives still present a noteworthy capacity to chelate iron, similarly to the chelating agent EDTA and to caffeic acid ( FIG. 2 ).
  • AntiOxCIN 2 and AntiOxCIN 4 displayed a higher iron chelation activity than caffeic acid itself.
  • AntiOxCINs chelating properties were not shared by MitoQ. This particular AntiOxCINs property may constitute per si an important feature for the treatment of mitochondrial and metabolic disorders involving iron overload.
  • mitochondrial AntiOxCINs uptake was assessed in isolated rat liver mitochondria (RLM) in response to the membrane potential.
  • AntiOxCINs can accumulate inside mitochondria driven by the ⁇ ( FIG. 3A ).
  • Different AntiOxCINs accumulation outlines within the mitochondrial matrix have been noticed. The process was found to be related with the increment of the spacer length and aromatic substitution pattern, and directly related with AntiOxCINs lipophilicity ( FIGS. 3B and 3C , Table 1). However, the linear increase of AntiOxCINs lipophilicity was not directly translated into an increase in the ratio of mitochondrial matrix accumulation ( FIG. 3B ).
  • AntiOxCIN 1 AntiOxCIN 2 ⁇ AntiOxCIN 6 ⁇ AntiOxCIN 3 (catechol series); AntiOxCIN 4 ⁇ AntiOxCIN 7 ⁇ AntiOxCIN 6 (pyrogallol series) ( FIG. 3C ).
  • AntiOxCIN 6 and AntiOxCIN 7 were the most lipophilic compounds, they exhibit a lower accumulation ratio probably due to the cut-off membrane effect.
  • AntiOxCIN 2 AntiOxCIN 6 and AntiOxCIN 4 displayed approximately the same accumulation ratio. All AntiOxCINs present an accumulation ratio comparable to that of MitoQ and higher than AntiOxCIN 1 ( FIG. 3C ).
  • Mitochondrial membranes possess a high concentration of polyunsaturated fatty acids that are particularly prone to oxidation as they are located near to ROS producing sites.
  • AntiOxCINs antioxidant performance on the protection of lipid peroxidation of RLM membranes was determined.
  • AntiOxCIN 2 (catechol series) and AntiOxCIN 2 (pyrogallol series), in FeSO 4 /H 2 O 2 /ascorbate assay, were found to be the most effective mitochondriotropic cinnamic derivatives in preventing mitochondria lipid peroxidation ( FIG. 4A ).
  • AntiOxCINs efficiency to prevent lipid peroxidation followed the same tendency ( FIGS. 4B and 5A -D).
  • AntiOxCINs vs MitoQ to inhibit lipid peroxidation in RLM decreased in the order MitoQ>AntiOxCIN 2 >AntiOxCIN 2 >>AntiOxCIN 4 ⁇ AntiOxCIN 5 >AntiOxCIN 6 z AntiOxCIN 3 >AntiOxCIN 1 >caffeic acid. Except for AntiOxCIN 2 , pyrogallol based AntiOxCINs ( FIGS. 4 and 5D ) were more effective in delaying lipid peroxidation membrane process having a higher performance than caffeic acid.
  • AntiOxCINs and MitoQ toxicity effects on the mitochondrial bioenergetics namely on RLM ⁇ and mitochondrial respiration parameters
  • the ALP represents the main component of the electrochemical gradient generated by mitochondrial respiration and accounts for more than 90% of the total available energy.
  • glutamate/malate (for complex I) and succinate (for complex II) were used as substrates.
  • the mitochondrial oxidative phosphorylation coupling index known as respiratory control ratio (RCR, state 3/state 4 respiration) and ADP/O index (the coupling between ATP synthesis and oxygen consumption) were also calculated.
  • AntiOxCINs and MitoQ were tested at antioxidant-relevant concentrations, with 10 ⁇ M being the highest concentration.
  • the mitochondrial bioenergetics data obtained for MitoQ was shown in (Table 2). The results obtained have been used for comparative analysis.
  • MitoQ (5 ⁇ M) also decreased the ability of ⁇ mitochondria to recover to a value similar to the control. ⁇ collapse after ADP addition was observed with 10 ⁇ M MitoQ, since no repolarization occurred after ADP-induced depolarization (Table 2).
  • the highest concentration used in AntiOxCINs toxicity studies was the one in which MitoQ completely disrupted mitochondrial bioenergetics.
  • the data of AntiOxCINs toxicity studies were shown in Tables 3 to 9.
  • AntiOxCIN 1 was also included in the mentioned studies for comparative analysis (Table 3).
  • the AntiOxCINs and MitoQ rates for state 2, state 3, state 4, oligomycin-inhibited respiration and mitochondrial respiration assays, and succinate are shown in FIG. 6A-H .
  • AntiOxCINs induced alterations on the respiratory chain in a dose-dependent manner.
  • AntiOxCINs increased state 2, state 4 and oligomycin-inhibited respiration at concentrations higher than 2.5 ⁇ M in a process that is mainly dependent on their lipophilicity and not relying on their aromatic pattern (catechol vs pyrogallol) ( FIG. 6B-H ).
  • AntiOxCINs induced dose-dependent alterations in the respiratory profile of isolated RLM. Probably some of the observed effects can result from a membrane permeabilization effect or a proton shuttling activity. This effect may lead to stimulation of non-phosphorylation respiration and to a small ALP depolarization. Consequently, for some AntiOxCINs the mitochondrial phosphorylative system, as assessed by the ADP/O ratio, was also affected.
  • AntiOxCINs ranking toxicity hierarchy on the mitochondrial bioenergetics apparatus was established: AntiOxCIN 1 ⁇ AntiOxCIN 2 ⁇ AntiOxCIN 3 ⁇ AntiOxCIN 6 (catechol series); AntiOxCIN 4 ⁇ AntiOxCIN 5 ⁇ AntiOxCIN 7 (pyrogallol series).
  • the AntiOxCINs mitochondrial toxicity observed at higher concentrations may be associated with the lipophilicity of the spacer and/or the presence of a TPP moiety and has little, if any, relation with their (catechol vs pyrogallol).
  • caffeic acid showed low toxicity toward the mitochondrial bioenergetic apparatus.
  • the presence of the TPP cation and a lipophilic spacer is essential for an efficient and sometimes extensive mitochondrial accumulation.
  • mitochondria-targeted antioxidants can disrupt mitochondrial respiration by causing damage in the inner mitochondrial membrane or by inhibiting the respiratory chain, ATP synthesis or export machinery.
  • the AntiOxCINs effects on mitochondrial permeability transition pore (mPTP) opening were evaluated. In general, less lipophilic AntiOxCINs had no effect on mPTP opening for all tested concentrations ( FIG. 7A-C ).
  • the cytotoxicity of two AntiOxCINs was assessed using monolayer cultures of human hepatocytes from hepatocellular carcinoma (HepG2) and SRB method ( FIG. 8A ). From the data, it was concluded that AntiOxCIN 6 (enfolding a catechol moiety) exhibited higher toxicity than AntiOxCIN 4 (harbouring a pyrogallol moiety) toward HepG2 cells ( FIG. 6A ). Remarkably, at concentrations higher than 2.5 ⁇ M AntiOxCIN 6 inhibited cell proliferation, while at concentrations higher than 100 ⁇ M AntiOxCIN 4 stimulated cell proliferation.
  • AntiOxCIN 6 toxicity based on its lipophilic properties (Table 1) and RLM accumulation rates ( FIG. 3 ), can be mediated by other processes mediated by the presence of catechol redox chemistry, a property that is often linked to deleterious effects.
  • the antioxidant cellular outline of AntiOxCIN 4 and AntiOxCIN 6 was assessed using monolayer cultures of human hepatocytes from hepatocellular carcinoma (HepG2) and two different oxidative stressors (250 ⁇ M FeSO 4 or 250 ⁇ M H 2 O 2 ) ( FIG. 8B ). Both AntiOxCINs significantly prevented the iron- and hydrogen peroxide-induced HepG2 cytotoxicity, expressed as cell proliferation outcome ( FIG. 6B ). The higher efficacy of AntiOxCIN 4 is in agreement with the data attained from TAC assays (Table 1) and RLM assays ( FIG. 4 ).
  • the morphological changes in mitochondrial network and nuclei chromatin condensation of AntiOxCIN 4 and AntiOxCIN 6 have been determined.
  • HepG2 cells were treated with AntiOxCINs for 48 h and then incubated with the mitochondrial ⁇ -dependent fluorescent probes TMRM and DNA dye Hoechst 33342.
  • the results showed that AntiOxCIN 4 (100 ⁇ M) and AntiOxCIN 6 (2.5 ⁇ M) did not induce nuclear morphological changes neither mitochondrial depolarization in HepG2 ( FIG. 8C ).
  • AntiOxCIN 1 led to a significant improvement of its mitochondriotropic properties.
  • Some AntiOxCINs have increased antioxidant activity, higher mitochondrial accumulation and lower toxicity.
  • AntiOxCIN 4 a pyrogallol-based analogue, is predicted to be a potential candidate for development of a first class drugs with therapeutic application in mitochondrial oxidative-related disorders.
  • AntiOxCIN 4 did not disturb mitochondrial morphology and polarization and showed a remarkable iron-chelation property not shared by MitoQ.
  • AntiOxCIN 4 may be useful to mitigate the effects of mitochondrial iron overload and/or reduce mitochondrial iron stores in oxidative stress related diseases and conditions.
  • the structural characterization of the compounds was attained by spectrometric methods of analysis.
  • 1 H and 13 C spectra NMR spectra were acquired at room temperature and recorded on a Bruker Avance III operating at 400 and 100 MHz, respectively. Chemical shifts are expressed in ⁇ (ppm) values relative to tetramethylsilane (TMS) as internal reference and coupling constants (J) are given in Hz. Assignments were also made from DEPT (distortionless enhancement by polarization transfer) (underlined values).
  • MS mass spectra
  • MS mass spectra
  • MS were recorded on a Bruker Microtof (ESI) or Varian 320-MS (EI) apparatus and referred in m/z (% relative) of important fragments.
  • reaction progress was assessed by thin layer chromatography (TLC) analyses on aluminium silica gel sheets 60 F254 plates (Merck, Darmstadt, Germany) in dichloromethane, ethyl acetate and dichloromethane/methanol, in several proportions. The spots were detected using UV detection (254 and 366 nm). Flash column chromatography was performed using silica gel 60 (0.040-0.063 mm) (Carlo Erba Retrac—SDS, France).
  • TLC thin layer chromatography
  • the general synthetic procedure for obtention of cinnamic acid amides was as follows: 3,4-dimethoxycinnamic acid (1), or 3,4,5-trimethoxycinnamic acid (2), (1 mmol), was dissolved in dichloromethane (10 ml) and triethylamine (2 mmol). To the stirred solution, kept in an ice bath, ethyl chloroformate (2 mmol) was added dropwise. After stirring 2 hours at room temperature, the mixture was cooled in an ice bath and the pretended aminoalcohol (2 mmol) was added dropwise. The reaction was stirred during 10 hours at room temperature.
  • the yield of (E)-3-(3,4-dimethoxyphenyl)-N-(6-hydroxyhexyl)prop-2-enamide (3) was 81%.
  • the yield of (E)-3-(3,4,5-trimethoxyphenyl)-N-(6-hydroxyhexyl)prop-2-enamide (4) was 88%.
  • the yield of (E)-3-(3,4-dimethoxyphenyl)-N-(8-hydroxyoctyl)prop-2-enamide (5) was 83%.
  • the (E)-3-(3,4,5-trimethoxyphenyl)-N-(8-hydroxyoctyl)prop-2-enamide (6) was yield: 89%.
  • the yield of (E)-3-(3,4-dimethoxyphenyl)-N-(10-hydroxydecyl)prop-2-enamide (7) was 78%.
  • the yield of (E)-3-(3,4,5-trimethoxyphenyl)-N-(10-hydroxydecyl)prop-2-enamide (8) was 69%.
  • the synthetic procedure for obtention of methanesulfonates derivatives was as follows: the cinnamic acid amide (3-8) (1 mmol) was dissolved in a mixture of tetrahydrofuran (10 ml) and triethylamine (2 mmol) and stirred at room temperature over a period of 10 minutes. Then, a solution of methanesulfonyl chloride (1.3 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 12 hours, the mixture was neutralized and the solvent partially evaporated.
  • the yield of (E)-(6-(3-(3,4-dimethoxyphenyl)prop-2-enamide)hexyl)methanesulfonate (9) was 87%.
  • the yield of (E)-(8-(3-(3,4-dimethoxyphenyl)prop-2-enamide)octyl)methanesulfonate (11) was 95%.
  • the yield of (E)-(8-(3-(3,4,5-trimethoxyphenyl)prop-2-enamide)octyl)methanesulfonate (12) was 96%.
  • the yield of (E)-(10-(3-(3,4-dimethoxyphenyl)prop-2-enamide)decyl)methanesulfonate (13) was 98%.
  • the yield of (E)-(10-(3-(3,4,5-trimethoxyphenyl)prop-2-enamide)decyl)methanesulfonate (14) was 96%.
  • triphenylphosphonium salts 15 and 16 were performed as follows: compound 9 or 10 (1 mmol) was thoroughly mixed with triphenylphosphine (1 mmol) in a microwave vial and sealed under argon. The reaction was placed under microwave irradiation at 150° C. for 1 hour and 30 minutes with magnetic stirring. Upon completion, the reaction mixture was cooled at room temperature and the crude product was purified by flash chromatography, using dichloromethane/methanol [9:1 ratio (v/v)] as elution system. The fractions containing the intended compound were combined and the solvent was evaporated.
  • the yield of (E)-(6-(3-(3,4-dimethoxyphenyl)prop-2-enamide)hexyl)triphenylphosphonium methanesulfonate was 73%.
  • the yield of (E)-(6-(3-(3,4,5-trimethoxyphenyl)prop-2-enamido)hexyl)triphenylphosphonium methanesulfonate (16) was 65%.
  • triphenylphosphonium salts 17-20 were performed as follows: methanesulfonate derivative (11-14) (1 mmol) was heated with triphenylphosphine (1 mmol) under argon atmosphere at 130° C. for 18 hours. The crude product was purified by flash chromatography, using dichloromethane/methanol [9:1 ratio (v/v)] as elution system. The fractions containing the pretended compound were combined and the solvent was evaporated. The resulting residue was then dissolved with a minimum amount of dichloromethane and triturated with excess ethyl ether. The solvent was decanted and the final solid residue was dried under vacuum to give the triphenylphosphonium methanesulfonate salt.
  • the yield of (E)-(8-(3-(3,4,5-trimethoxyphenyl)acrylamido)octyl)triphenylphosphonium methanesulfonate (18) was: 96%.
  • the yield of (E)-(10-(3-(3,4-dimethoxyphenyl)acrylamido)decyl)triphenylphosphonium methanesulfonate (19) was 61%.
  • the yield (E)-(10-(3-(3,4,5-trimethoxyphenyl)acrylamido)decyl)triphenylphosphonium methanesulfonate (20) was 69%.
  • the general synthetic procedure for obtention of mitochondriotropic antioxidants was performed as follows: the triphenylphosphonium compound (15-20) (1 mmol) was dissolved in anhydrous dichloromethane (15 ml). The reaction mixture was stirred under argon and cooled at a temperature below ⁇ 70° C. To this solution, boron tribromide (3 mmol, 1 M solution in dichloromethane) was added. Once the addition was completed, the reaction was kept at ⁇ 70° C. for 10 minutes and then allowed to warm to the room temperature with continuous stirring for 12 hours. After BBr3 destruction with water, the purification process was carried out straightforward. After water removing the resulting product was dissolved in methanol and dried over anhydrous Na 2 SO 4 , filtered and the solvent evaporated.
  • the yield of (E)-(6-(3-(3,4-dihydroxyphenyl)prop-2-enamido)hexyl)triphenylphosphonium methanesulfonate (AntiOxCIN 2 ) was 30%.
  • the yield of (E)-(8-(3-(3,4-dihydroxyphenyl)acrylamido)octyl)triphenylphosphoniummethanesulfonate (AntiOxCIN 3 ) was 55%.
  • the yield of (E)-(10-(3-(3,4-dihydroxyphenyl)acrylamido)decyl)triphenylphosphonium methanesulfonate (AntiOxCIN 6 ) was 80%.
  • the yield of (E)-(6-(3-(3,4,5-trihydroxyphenyl)prop-2-enamido)hexyl)triphenylphosphonium methanesulfonate (AntiOxCIN 4 ) was 50%.
  • the yield of (E)-(10-(3-(3,4,5-trihydroxyphenyl)acrylamido)decyl)triphenylphosphonium methanesulfonate (AntiOxCIN 7 ) was 53%.
  • the radical scavenging activity of AntiOxCINs was evaluated by means of total antioxidant capacity assays based on DPPH., ABTS. + and GO. radicals. All these methods involved the spectrophotometric measurement of the absorbance decrease resulting from radical (DPPH., ABTS. + or GO.) deactivation with an antioxidant. The results were expressed in IC 50 , which is defined as the minimum antioxidant concentration necessary to reduce the amount of radical by 50%. Antioxidant assays were performed in a multiplate reader (Powerwave XS Microplate Reader) of Bio-Tech instruments.
  • the DPPH. radical scavenging activity was performed as follows: solutions of the test compounds with increasing concentrations (range between 0 ⁇ M and 500 ⁇ M) were prepared in ethanol. A DPPH′ ethanolic solution (6.85 mM) was also prepared and then diluted to reach the absorbance of 0.72 ⁇ 0.02 at 515 nm. Each compound solution (20 ⁇ L) was added to 180 ⁇ L of DPPH′ solution in triplicate, and the absorbance at 515 nm was recorded minutely over 45 minutes. The percent inhibition of the radical was based on comparison between the blank (20 ⁇ L of ethanol and 180 ⁇ L of DPPH′ solution), which corresponded to 100% of radical, and test compounds solutions. Dose-response curves were established for the determination of IC 50 values. Data are means ⁇ SEM of three independent experiments.
  • the ABTS. + scavenging activity was evaluated as follows: ethanolic solutions of the test compounds with increasing concentrations (range between 10 ⁇ M and 500 ⁇ M) were prepared. ABTS. + radical cation solution was obtained by addition of 150 mM aqueous potassium persulfate solution (163 ⁇ L) to 10 mL of 7 mM aqueous ABTS solution followed by storage in the dark at room temperature for 16 h (2.45 mM final concentration). The solution was then diluted in ethanol to reach the absorbance of 0.72 ⁇ 0.02. After addition of the compound (20 ⁇ L), in triplicate, to ABTS. + solution (180 ⁇ L) the spectrophotometric measurement was carried out each minute over 15 minutes.
  • the percent inhibition of radical was based on comparison between the blank (20 ⁇ L of ethanol and 180 ⁇ L of ABTS. + solution), which corresponds to 100% of radical, and test compounds solutions. Dose-response curves were established for the determination of IC 50 values. Data are means ⁇ SEM of three independent experiments.
  • the GO′ scavenging activity was evaluated as follows: solutions of test compounds with concentrations from 5 ⁇ M to 75 ⁇ M were prepared in ethanol. An ethanolic solution of 5 mM GO′ was prepared and diluted to reach the absorbance of 1.00 ⁇ 0.02 at 428 nm. The addition (20 ⁇ L) in triplicate of compound solution to GO. solution (180 ⁇ L) was followed by absorbance measurement at 428 nm over 30 minutes, in the dark, at room temperature. The percent inhibition of radical was based on comparison between the blank (20 ⁇ L of ethanol and 180 ⁇ L of GO; solution), which corresponds to 100% of radical, and test compounds solutions. Dose-response curves were established for the determination of IC 50 values. Data are means ⁇ SEM of three independent experiments.
  • the redox and lipophilic properties of AntiOxCINs were evaluated by electrochemical techniques.
  • the electrochemical analytical data was obtained using a computer controlled potentiostat Autolab PGSTAT302N (Metrohm Autolab, Utrecht, Netherlands).
  • CV cyclic voltammetry
  • DPV Differential pulse voltammetry
  • the electrochemical signals were monitored by the General Purpose Electrochemical System (GPES) version 4.9, software package. All electrochemical experiments were performed at room temperature in an electrochemical cell that was placed in a Faraday cage in order to minimize the contribution of background noise to the analytical signal.
  • GPES General Purpose Electrochemical System
  • GCE glassy carbon electrode
  • the evaluation of AntiOxCINs lipophilic properties was performed as follows: the electrochemical cell was a four-electrode system with arrays of micro liquid-liquid interfaces ( ⁇ lTIES) containing two Ag/AgCl reference electrodes and two counter electrodes of Pt, one in each phase.
  • the microporous membrane was sealed with a fluorosilicone sealant (Dow Corning 730) onto a glass cylinder which was filled with 4.0 mL of the aqueous phase, where the aliquots of AntiOxCINs solutions were added.
  • the membrane was then immersed into the organic phase contained in the cell.
  • the organic phase reference solution (a 2 mM BTPPACI+2 mM NaCl aqueous solution) was mechanically stabilized
  • the aqueous supporting electrolyte solution was a Tris-HCl buffer 10 mM pH 7.0.
  • AntiOxCINs iron chelating properties were evaluated by the spectrophotometric ferrozine method performed in a multiplate reader (Powerwave XS Microplate Reader) of Bio-Tech instruments.
  • the AntiOxCINs iron chelating properties were evaluated as follows: in each well, a solution of the test compound (100 ⁇ M) and ammonium iron (II) sulphate in ammonium acetate (20 ⁇ M) were added, incubated for 10 min and the absorbance was read at 562 nm. Then, a freshly prepared solution of ferrozine (5 mM) was added to each well (96 ⁇ M final concentration). After a new incubation at 37° C. for 10 min period, the absorbance of [Fe(ferrozine) 3 ] 2+ complex was measured at 562 nm. Blank wells were run using DMSO instead of the test compounds. EDTA was used as a reference.
  • RLM rat liver mitochondria
  • the mitochondrial AntiOxCINs uptake was evaluated.
  • the AntiOxCINs mitochondria uptake by energized RLM was evaluated as follows: RLM (0.5 mg protein/mL) were incubated with AntiOxCINs at 37° C. under constant stirring in 1 mL of KCl medium (120 mM KCl, 10 mM HEPES, pH 7.2 and 1 mM EGTA). Five sequential 1 ⁇ M additions of each AntiOxCINs were performed to calibrate the electrode response in the presence of rotenone (1.5 ⁇ M). Then, succinate (10 mM) was added to generate AN. Valinomicin (0.2 ⁇ g/mL) was added at the end of the assay to dissipate AN.
  • the measurements were performed with an ion-selective electrode, which measure the distribution of tetraphenylphosphonium cation (TPP + ) and Ag/AgCl 2 electrode as reference.
  • the mitochondrial accumulation ratio was calculated by the disappearance of AntiOxCINs from extra- to intramitochondrial medium assuming an intramitochondrial volume of 0.5 ⁇ L/mg protein and a binding correction for the mitochondrial uptake of TPP compounds.
  • the effect of AntiOxCINs on RLM lipid peroxidation was measured by thiobarbituric acid reactive species (TBARS) assay as follows: RLM (2 mg protein/ml) were incubated in 0.8 mL medium containing 100 mM KCl, 10 mM Tris-HCl and pH 7.6, at 37° C., supplemented with 5 mM glutamate/2.5 mM malate as substrate. RLM were incubated for 5 min period with each AntiOxCINs (5 ⁇ M) and then mitochondria were exposed to oxidative stress condition by the addition of 100 ⁇ M FeSO 4 /500 ⁇ M H 2 O 2 /5 mM ascorbate for 15 min at 37° C.
  • TBARS thiobarbituric acid reactive species
  • the effect of AntiOxCINs on RLM lipid peroxidation was measured by a second methodology as follows: the oxygen consumption of 2 mg RLM, in a total volume of 1 mL of a reaction medium consisting of 100 mM KCl, 10 mM Tris-HCl and pH 7.6, using glutamate/malate (5 mM/2.5 mM) as respiratory substrate, was monitored at 37° C. with a Clark oxygen electrode. RLM were incubated for 5 min period with each AntiOxCINs (5 ⁇ M) and then lipid peroxidation process started by adding 10 mM ADP and 0.1 mM FeSO 4 (final concentrations).
  • the saturated concentration of O 2 in the incubation medium was assumed to be 217 ⁇ M at 37° C.
  • Time-dependent changes on oxygen consumption resulting from peroxidation of RLM membranes by a pro-oxidant pair (1 mM ADP/0.1 mM FeSO 4 ) were recorded.
  • the traces are means ⁇ SEM recording from six independent experiments.
  • the time lag-phase associated with the slower oxygen consumption that followed the addition of ADP/Fe 2+ was used to measure the effectiveness of AntiOxCINs to prevent lipid peroxidation.
  • the evaluation of AntiOxCINs effect on mitochondrial respiration was performed as follows: the respiration of isolated RLM was evaluated polarographically with a Clark-type oxygen electrode, connected to a suitable recorder in a 1 mL thermostated water-jacketed chamber with magnetic stirring, at 37° C. 1 .
  • the standard respiratory medium consisted of 130 mM sucrose, 50 mM KCl, 5 mM KH 2 PO 4 , 5 mM HEPES (pH 7.3) and 10 ⁇ M EGTA.
  • oligomycin (2 ⁇ g/ml) inhibited ATP-synthase and originated the oligomycin-inhibition respiration state. Finally, 1 ⁇ M FCCP was added to induce uncoupled respiration.
  • the RCR was of 6.42 ⁇ 0.57 and 4.90 ⁇ 0.66 for the control experiments, with glutamate-malate or succinate as respiratory substrates, respectively.
  • the ADP/O index was 2.64 ⁇ 0.10 and 1.58 ⁇ 0.09 with the same respiratory substrates, respectively Data are means are means ⁇ SEM of seven independent experiments.
  • the evaluation of AntiOxCINs effect on mitochondrial transmembrane electric potential ( ⁇ ) was performed as follows: the mitochondrial transmembrane electric potential ( ⁇ ) was estimated through the evaluation of fluorescence changes of safranine (5 ⁇ M) and was recorded on a spectrofluorometer operating at excitation and emission wavelengths of 495 and 586 nm, with a slit width of 5 nm.
  • Increasing concentrations of AntiOxCINs were added to the reaction medium (200 mM sucrose, 1 mM KH 2 PO 4 , 10 mM Tris (pH 7.4) and 10 ⁇ M EGTA) containing respiratory substrates glutamate/malate (5 mM and 2.5 mM respectively) or succinate (5 mM) and RLM (0.5 mg in 2 mL final volume) and allowed to incubate for a 5 min period prior to initiate the assay, at 25° C.
  • safranine (5 ⁇ M) and ADP 25 nmol
  • the effect of AntiOxCINs on mitochondrial permeability transition pore opening were measured as follows: mitochondrial swelling was estimated by measuring the alterations of light scattered from a mitochondrial suspension, as monitored spectrophotometrically at 540 nm. Increasing concentrations of AntiOxCINs (2.5-10 ⁇ M) were added to the reaction medium (200 mM sucrose, 1 mM KH 2 PO 4 , 10 mM Tris (pH 7.4), 5 mM succinate and 10 ⁇ M EGTA supplemented with 1.5 ⁇ M rotenone), in the presence of RLM (1 mg), and allowed to incubate for a 5 min period before the assay.
  • the reaction medium 200 mM sucrose, 1 mM KH 2 PO 4 , 10 mM Tris (pH 7.4), 5 mM succinate and 10 ⁇ M EGTA supplemented with 1.5 ⁇ M rotenone
  • the cytotoxicity profile of AntiOxCIN 4 and AntiOxCIN 6 was evaluated in human hepatocellular carcinoma HepG2 cells.
  • Human hepatocellular carcinoma HepG2 cells were cultured in high-glucose medium composed by Dulbecco's modified Eagle's medium (DMEM; D5648) supplemented with sodium pyruvate (0.11 g/L), sodium bicarbonate (1.8 g/L) and 10% fetal bovine serum (FBS) and 1% of antibiotic penicillin-streptomycin 100 ⁇ solution. Cells were maintained at 37° C. in a humidified incubator with 5% CO 2 . HepG2 cells were seeded at density of 4 ⁇ 10 4 cells/mL and grown for 24 hours before treatment.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • the cytotoxicity screening was performed as follows: cells were placed on 48-well plate (2 ⁇ 10 4 cells/500 ⁇ L) and then were incubated during 48 hour with AntiOxCIN 4 and AntiOxCIN 6 concentrations ranging 25 ⁇ M to 500 ⁇ M or 0.5 ⁇ M to 25 ⁇ M, respectively. After incubation, sulforhodamine B (SRB) assay was used for cell density determination based on the measurement of cellular protein content. Briefly, after incubation, the medium was removed and wells rinsed with PBS (1 ⁇ ). Cells were fixed by adding 1% acetic acid in 100% methanol for at least 2 hours at ⁇ 20° C.
  • SRB sulforhodamine B
  • the cellular antioxidant profile of AntiOxCIN 4 and AntiOxCIN 6 was evaluated in human hepatocellular carcinoma HepG2 cells.
  • the cellular morphological alterations induced by AntiOxCIN 4 and AntiOxCIN 6 in human hepatocellular carcinoma HepG2 cells were assessed using vital epifluorescence microscopy.
  • the detection of morphological alterations, including chromatin condensation and mitochondrial polarization and distribution by vital epifluorescence microscopy was performed as follows: cells were placed in 6-well plates with a glass coverslip per well (8 ⁇ 10 4 cells/2 mL) and then treated with non-toxic concentrations of AntiOxCIN 4 or AntiOxCIN 6 for 48 hours.
  • the mitochondrial network was stained with TMRM (100 nM) while nuclei were stained with Hoechst 33342 (1 ⁇ g/mL), to detect apoptotic chromatin condensation, in HBSS (NaCl 137 mM, KCl 5.4 mM, NaHCO 3 4.2 mM, Na 2 HPO 4 0.3 mM, KH 2 PO 4 0.4 mM, CaCl 2 1.3 mM, MgCl 2 0.5 mM, MgSO 4 0.6 mM, and D-glucose 5.6 mM, pH 7.4) at 37° C. under dark conditions.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • any particular embodiment of the present invention may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects are excluded are not set forth explicitly herein.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130272983A1 (en) 2005-11-08 2013-10-17 Universite Joseph Fourier-Grenoble 1. Para-Coumaric Acid or Para-Hydroxycinnamic Acid Derivatives and their Use in Cosmetic or Dermatological Compositions

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080199502A1 (en) 2005-04-08 2008-08-21 Dominic Tessier Antimicrobial Solution Comprising a Metallic Salt and a Surfactant
EP2179984A1 (en) * 2008-10-27 2010-04-28 Congenia S.r.l. Acrylamido derivatives useful as inhibitors of the mitochondrial permeability transition
KR101719556B1 (ko) 2011-03-30 2017-03-24 주식회사 레고켐 바이오사이언스 신규한 세파로스포린 유도체 및 이를 함유하는 의약 조성물
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130272983A1 (en) 2005-11-08 2013-10-17 Universite Joseph Fourier-Grenoble 1. Para-Coumaric Acid or Para-Hydroxycinnamic Acid Derivatives and their Use in Cosmetic or Dermatological Compositions

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
Alam MA, et al. Hydroxycinnamic acid derivatives: a potential class of natural compounds for the management of lipid metabolism and obesity. Nutr Metab (Lond). Apr. 11, 2016;13:27. doi: 10.1186/s12986-016-0080-3. eCollection 2016. Retirado da net: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827240/ (Mar. 22, 2017).
Anders MW. Exploiting endobiotic metabolic pathways to target xenobiotic antioxidants to mitochondria. Mitochondrion. Sep. 2013;13(5):454-63. doi: 10.1016/j.mito.2012.10.015. Epub Nov. 1, 2012.
Benfeito S, Oliveira C, Soares P, Fernandes C, Silva T, Teixeira J, et al. Antioxidant therapy: still in search of the magic bullet'. Mitochondrion 2013, 13(5): 427-435.
Benfeito S; Oliveira C; Soares P; Fernandes C; Silva T; Teixeira J et al., "Antioxidant therapy: still in search of the 'magic bullet", Mitochondrion, (2013), vol. 13, No. 5, pp. 427-435, XP028696391 [ID] 1-4,9-11,13,23-47 * abstract * [A] 5-8,12,14-22.
BENFEITO SOFIA; OLIVEIRA CATARINA; SOARES PEDRO; FERNANDES CARLOS; SILVA TIAGO; TEIXEIRA JOS�; BORGES FERNANDA: "Antioxidant therapy: Still in search of the ‘magic bulle", MITOCHONDRION, ELSEVIER, AMSTERDAM, NL, vol. 13, no. 5, 1 January 1900 (1900-01-01), NL, pages 427 - 435, XP028696391, ISSN: 1567-7249, DOI: 10.1016/j.mito.2012.12.002
Brovarets, V. S. et al, "Synthesis of [1-(acylamino)ethenyl]triphenylphosphonium salts", CA, Chemical Abstracts Service, Columbus, Ohio, US, Database accession No. 1993:102080, URL: STN, XP002777033 [X] 1,4 * abstract * , 1993.
Chen YS, et al. Biological and structural studies of phosphonium ‘masked thiolate’ compounds. Eur J Med Chem. Jan. 5, 2017;125:528-537. doi: 10.1016/j.ejmech.2016.08.025.
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 5 January 2018 (2018-01-05), BROVARETS, V. S. ET AL: "Synthesis of [1-(acylamino)ethenyl]triphenylphosphonium salts", XP002777033, retrieved from STN
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 5 January 2018 (2018-01-05), TEIXERA JOSE ET AL: "Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold.", XP002777032
Melissa Millard et al, "A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic Cancers", Journal of Medicinal Chemistry, (Nov. 27, 2013), vol. 56, No. 22, doi:10.1021/im4012438, ISSN 0022-2623, pp. 9170-9179, XP055438311 [I] 1-4,23-47 * Scheme 1* , 2013.
MELISSA MILLARD, JOHN D. GALLAGHER, BOGDAN Z. OLENYUK, NOURI NEAMATI: "A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic Cancers", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 56, no. 22, 27 November 2013 (2013-11-27), US, pages 9170 - 9179, XP055438311, ISSN: 0022-2623, DOI: 10.1021/jm4012438
Murphy MP. Antioxidants as therapies: can we improve on nature? Free Radical Biology and Medicine 2014, 66: 20-23.
Prasipan N et al, "N-1 and C-2 Substituted Tryptophans as Potential Inhibitors of Sickle Cell Hemoglobin Gelation", Journal of Heterocyclic Chemistry, Wiley-Blackwell Publishing, Inc, US, (Mar. 1, 1992), vol. 29, No. 2, doi:10.1002/JHET.5570290210, ISSN 0022-152X, pp. 335-341, XP000984090 [X] 1-4,7,9,11,12 * Scheme 2 * , 1992.
PRASIPAN N, ET AL.: "N-1 AND C-2 SUBSTITUTED TRYPTOPHANS AS POTENTIAL INHIBITORS OF SICKLE CELL HEMOGLOBIN GELATION", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 29, no. 02, 1 March 1992 (1992-03-01), US, pages 335 - 341, XP000984090, ISSN: 0022-152X, DOI: 10.1002/jhet.5570290210
Silva T, et al. Caffeic acid derivatives, analogs and applications: a patent review (2009-2013). Expert Opin Ther Pat. Nov. 2014;24(11):1257-70. doi: 10.1517/13543776.2014.959492. Epub Oct. 4, 2014.
Smith RA, Hartley RC, Cocheme HM, Murphy MP. Mitochondrial pharmacology. Trends in pharmacological sciences 2012, 33(6): 341-352.
Teixeira J; Soares P; Benfeito S; Gaspar A; Garrido J; Murphy MP et al., "Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold", Free Radical Research, (2012), vol. 46, No. 5, pp. 600-611.
Teixera Jose et al, "Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold.", CA, Chemical Abstracts Service, Columbus, Ohio, US, Database accession No. 2012:447889, XP002777032 [XD] 1-4,10,23-36,39-45 * abstract * [A] 19,20,22 [I] 5-9,11-18,21,37,38,46,47 , 2012.
Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annual review of pathology 2010, 5: 297-348.

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